Metamorphic evolution of the Great Slave Lake shear zone

Funder: Natural Environment Research Council; Id: http://dx.doi.org/10.13039/501100000270Funder: Natural Sciences and Engineering Research Council of Canada; Id: http://dx.doi.org/10.13039/501100000038Abstract: The Palaeoproterozoic Great Slave Lake shear zone (GSLsz) is a crustal‐scale strike‐slip structure, with a total length of >1,000 km and a width of ~25 km, that separates the Archean Rae and Slave cratons. The range of metamorphic rocks now exposed at the surface encompasses granulite facies mylonite through to lower‐greenschist facies ultramylonite and cataclasite, providing a potential type example of fault‐zone structure in the middle and lower crust. However, the metamorphic evolution of the units remains poorly quantified, hindering detailed structural and tectonic interpretations. Here, we use phase equilibria modelling and thermobarometry to determine the metamorphic conditions recorded by pelitic, mafic and felsic GSLsz mylonites. Samples from the entire range of granulite–greenschist facies units preserve evidence for nested clockwise pressure–temperature paths that are consistent with a single orogenic cycle. Our findings indicate that the northern Rae margin underwent pervasive crustal thickening with peak pressures in metasedimentary rocks reaching ~1.1 GPa. The crustal thermal gradient at the onset of thickening was ~650°C/GPa, whereas the final stages of equilibrium recorded by fine‐grained matrix minerals in all samples collectively define a metamorphic field gradient of ~1,000°C/GPa. Deformation microstructures are consistent with the main phase of dextral shear having been synchronous with or following peak metamorphism. The history of metamorphism and exhumation of the GSLsz is consistent with the Sibson–Scholz model for shear zones, with a narrowing of the deforming zone and the progressive overprinting of higher‐grade assemblages during exhumation through shallower crustal levels

Trends in liver transplantation for primary biliary cirrhosis in the Netherlands 1988-2008

Background: A decrease in the need for liver transplantations (LTX) in Primary Biliary Cirrhosis (PBC), possibly related to treatment with ursodeoxycholic acid (UDCA), has been reported in the USA and UK. The aim of this study was to assess LTX require

Association between FTO variant and change in body weight and its interaction with dietary factors: the DiOGenes study

Although FTO is an established obesity-susceptibility locus, it remains unknown whether it influences weight change in adult life and whether diet attenuates this association. Therefore, we investigated the association of FTO-rs9939609 with changes in weight and waist circumference (WC) during 6.8 years follow-up in a large-scale prospective study and examined whether these associations were modified by dietary energy percentage from fat, protein, carbohydrate, or glycemic index (GI). This study comprised data from five countries of European Prospective Investigation into Cancer and Nutrition (EPIC) and was designed as a case-cohort study for weight gain. Analyses included 11,091 individuals, of whom 5,584 were cases (age (SD), 47.6 (7.5) years), defined as those with the greatest unexplained annual weight gain during follow-up and 5,507 were noncases (48.0 (7.3) years), who were compared in our case-noncase (CNC) analyses. Furthermore, 6,566 individuals (47.9 (7.3) years) selected from the total sample (all noncases and 1,059 cases) formed the random subcohort (RSC), used for continuous trait analyses. Interactions were tested by including interaction terms in the models. In the RSC-analyses, FTO-rs9939609 was associated with BMI (β (SE), 0.17 (0.08) kg·m(-2)/allele; P = 0.034) and WC (0.47 (0.21) cm/allele; P = 0.026) at baseline, but not with weight change (5.55 (12.5) g·year(-1)/allele; P = 0.66) during follow up. In the CNC-analysis, FTO-rs9939609 was associated with increased risk of being a weight-gainer (OR: 1.1; P = 0.045). We observed no interaction between FTO-rs9939609 and dietary fat, protein and carbohydrate, and GI on BMI and WC at baseline or on change in weight and WC. FTO-rs9939609 is associated with BMI and WC at baseline, but association with weight gain is weak and only observed for extreme gain. Dietary factors did not influence the associations

User-Centered App Adaptation of a Low-Intensity E-Mental Health Intervention for Syrian Refugees

Introduction: The aim of this study is to describe the initial stages of the iterative and user-centered mobile mental health adaptation process of Step-by-Step (SbS), a modularized and originally web-based e-mental health intervention developed by the World Health Organization (WHO). Given the great need for improving the responsiveness and accessibility of health systems in host countries, the EU-funded STRENGTHS consortium studies the adaptation, implementation and scaling-up of SbS for Syrian refugees in Germany, Sweden and Egypt. Using early prototyping, usability testing and identification of barriers to implementation, the study demonstrates a user-centered process of contextual adaptation to the needs and expectations of Syrian refugees.Materials and Methods:N = 128 adult Syrian refugees residing in Germany, Sweden and Egypt took part in qualitative assessments. Access, usage, and potential barriers regarding information and communication technologies (ICTs) were assessed in free list interviews. Interactive prototypes of the app were presented in key informant interviews and evaluated on usability, user experience and dissemination strategies. Focus groups were conducted to verify the results. The interview protocols were analyzed using inductive and deductive thematic analysis.Results: The use of digital technologies was found to be widespread among Syrian refugees. Technical literacy and problems with accessing the internet were common barriers. The majority of the respondents reacted positively to the presented app prototypes, stressing the potential health impact of the intervention (n = 28; 78%), its flexibility and customizability (n = 19; 53%) as well as the easy learnability of the app (n = 12; 33%). Aesthetic components (n = 12; 33%) and the overall length and pace of the intervention sessions (n = 9; 25%) were criticized in regard to their negative impact on user motivation. Acceptability, credibility, and technical requirements were identified as main barriers to implementation.Discussion: The study provided valuable guidance for adapting the app version of SbS and for mobile mental health adaptation in general. The findings underline the value of contextual adaptation with a focus on usability, user experience, and context specific dissemination strategies. Related factors such as access, acceptability and adherence have major implications for scaling-up digital interventions

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

Smchd1-Dependent and -Independent Pathways Determine Developmental Dynamics of CpG Island Methylation on the Inactive X Chromosome

X chromosome inactivation involves multiple levels of chromatin modification, established progressively and in a stepwise manner during early development. The chromosomal protein Smchd1 was recently shown to play an important role in DNA methylation of CpG islands (CGIs), a late step in the X inactivation pathway that is required for long-term maintenance of gene silencing. Here we show that inactive X chromosome (Xi) CGI methylation can occur via either Smchd1-dependent or -independent pathways. Smchd1-dependent CGI methylation, the primary pathway, is acquired gradually over an extended period, whereas Smchd1-independent CGI methylation occurs rapidly after the onset of X inactivation. The de novo methyltransferase Dnmt3b is required for methylation of both classes of CGI, whereas Dnmt3a and Dnmt3L are dispensable. Xi CGIs methylated by these distinct pathways differ with respect to their sequence characteristics and immediate chromosomal environment. We discuss the implications of these results for understanding CGI methylation during development

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Scalable psychological interventions for Syrian refugees in Europe and the Middle East: STRENGTHS study protocol for a prospective individual participant data meta-analysis

Introduction: The World Health Organization's (WHO) scalable psychological interventions, such as Problem Management Plus (PM+) and Step-by-Step (SbS) are designed to be cost-effective non-specialist delivered interventions to reduce symptoms of common mental disorders, such as anxiety, depression and post-traumatic stress disorder (PTSD). The STRENGTHS consortium aims to evaluate the effectiveness, cost-effectiveness and implementation of the individual format of PM+ and its group version (gPM+), as well as of the digital SbS intervention among Syrian refugees in seven countries in Europe and the Middle East. This is a study protocol for a prospective individual participant data (IPD) meta-analysis to evaluate (1) overall effectiveness and cost-effectiveness and (2) treatment moderators of PM+, gPM+ and SbS with Syrian refugees. Methods and analysis: Five pilot randomised controlled trials (RCTs) and seven fully powered RCTs conducted within STRENGTHS will be combined into one IPD meta-analytic dataset. The RCTs include Syrian refugees of 18 years and above with elevated psychological distress (Kessler Psychological Distress Scale (K10>15)) and impaired daily functioning (WHO Disability Assessment Schedule 2.0 (WHODAS 2.0>16)). Participants are randomised into the intervention or care as usual control group, and complete follow-up assessments at 1-week, 3-month and 12-month follow-up. Primary outcomes are symptoms of depression and anxiety (25-item Hopkins Symptom Checklist). Secondary outcomes include daily functioning (WHODAS 2.0), PTSD symptoms (PTSD Checklist for DSM-5) and self-identified problems (PSYCHLOPS). We will conduct a one-stage IPD meta-analysis using linear mixed models. Quality of evidence will be assessed using the GRADE approach, and the economic evaluation approach will be assessed using the CHEC-list. Ethics and dissemination: Local ethical approval has been obtained for each RCT. This IPD meta-analysis does not require ethical approval. The results of this study will be published in international peer-reviewed journals